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Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.

The lipin phosphatidic acid phosphatase (PAP) enzymes are required for triacylglycerol (TAG) synthesis from glycerol 3-phosphate in most mammalian tissues. The 3 lipin proteins (lipin 1, lipin 2, and lipin 3) each have PAP activity, but have distinct tissue distributions, with lipin 1 being the predominant PAP enzyme in many metabolic tissues. One exception is the small intestine, which is unique in expressing exclusively lipin 2 and lipin 3. TAG synthesis in small intestinal enterocytes utilizes 2-monoacylglycerol and does not require the PAP reaction, making the role of lipin proteins in enterocytes unclear. Enterocyte TAGs are stored transiently as cytosolic lipid droplets or incorporated into lipoproteins (chylomicrons) for secretion. We determined that lipin enzymes are critical for chylomicron biogenesis, through regulation of membrane phospholipid composition and association of apolipoprotein B48 with nascent chylomicron particles. Lipin 2/3 deficiency caused phosphatidic acid accumulation and mammalian target of rapamycin complex 1 (mTORC1) activation, which were associated with enhanced protein levels of a key phospholipid biosynthetic enzyme (CTP:phosphocholine cytidylyltransferase α) and altered membrane phospholipid composition. Impaired chylomicron synthesis in lipin 2/3 deficiency could be rescued by normalizing phospholipid synthesis levels. These data implicate lipin 2/3 as a control point for enterocyte phospholipid homeostasis and chylomicron biogenesis.

Dental problems are among the most frequently reported health issues of drug users. This study describes, among the largest population of methamphetamine (MA) users to date (N = 459, including both HIV-negative and HIV-positive participants) oral hygiene practice, dental care access, and dental quality of life. A matched control group from the Third National Health and Nutrition Examination Survey was utilized. Findings conclusively establish that MA users have severe oral health deficits compared to the general population: they are 3.5 times more likely to experience painful toothaches, 6.6 times to experience difficulty eating, and 8.6 times to be self-conscious due to dental appearance. HIV-positive users were more likely to have regular dental visits than HIV-negative users. Severity of use (both high-frequency use as well as injection as the method) was associated with poorer oral health care. Despite the magnitude of the need, few MA users receive the needed care.

BackgroundThe authors used a large community sample of methamphetamine (MA) users to verify the patterns and severity of dental disease and establish a hierarchy of caries susceptibility by tooth type and tooth surface.MethodsUsing a stratified sampling approach, 571 MA users received comprehensive oral examinations and psychosocial assessments. Three calibrated dentists characterized dental and periodontal disease by using National Health and Nutrition Examination Survey protocols. The authors also collected data on substance use history and other attributes linked to dental disease.ResultsOn all dental outcome measures, MA users evidenced high dental and periodontal disease, with older (≥ 30 years) and moderate or heavy MA users disproportionately affected. Women had higher rates of tooth loss and caries, as well as a greater prevalence of anterior caries. Current cigarette smokers were more likely to manifest 5 or more anterior surfaces with untreated caries and 3 or more teeth with root caries. Nearly 3% were edentulous, and a significant percentage (40%) indicated embarrassment with their dental appearance.ConclusionsMA users have high rates of dental and periodontal disease and manifest a dose-response relationship, with greater levels of MA use associated with higher rates of dental disease. Women and current cigarette smokers are affected disproportionately. The intraoral patterns and hierarchy of caries susceptibility in MA users are distinctive.Practical implicationsThe prevalence and patterns of dental and periodontal disease could be used to alert dentists to possible covert MA use and to plan treatment. Concerns about dental appearance have potential as triggers for behavioral interventions.

Neglected tropical diseases comprise 20 communicable diseases of different pathogenic origins endemic to tropical and subtropical regions. These diseases disproportionately affect the world's poorest and most marginalized populations. (1) The [...]